Dr Chen - FTO paper 2.0

Surfing the internet over the weekend as you do in lock down I came across an interesting article from the American Society of Hematology titled, “RNA modifications in hematopoietic malignancies: A new research frontier”

This independent work was published on 22 June 2021. Its author is no other than RAC SAB member, Jianjun Chen of the City of Hope. It builds on his previous work in June 2020 identifying Bisantrene as the most potent inhibitor of FTO. I believe this paper adds more value to confirming @mason14s belief of Bisantrenes true mechanism of action.

The paper goes into quite a lot of detail discussing the therapeutic potential of targeting RNA modifications for the treatment of hematopoietic malignancies, especially AML.

Detail from the paper that peaked my interest include:

m6A is deposited by “writer” proteins, removed by “eraser” proteins and recognised and bound by “reader” proteins to exert its biological functions. The role of FTO, a major m6A “eraser” in normal hematopoiesis has yet to be investigated – (RAC will find out soon enough with trials commencing shortly).

The m6A modification is first linked with AML by a study reporting the oncogenic role of FTO in AML. Analysis of a microarray dataset of over 100 human AML patient samples revealed that FTO is uberrantly upregulated (thus using an eraser such as bisantrene and inhibiting FTO in combination should bring back some sensitivities of other targeted therapies).

Overexpression of FTO promotes leukemia cell growth / proliferation in vitro and accelerates leukemogeni in vivo, where FTO depletion suppresses leukemia cell growth / proliferation and delays leukemogenis.

There is evidence in combining hypomethylating agents (such as azacytidine and decitabine) in inhibiting AML cell survival in vitro and vivo. These finding highlight the therapeutic potential of targeting FTO in AML. (note our AML trial is using combination of bisantrene and decitabine).

Pharmacological inhibition of FTO by CS1 (Bisantrene) is proven to downregulate the expression of immune genes, especially LILRB4 which is expressed 40-50 fold higher than PD-L1 and PD-L2 sensitising AML cells to T cell cytotoxicity by overcoming immune evasion.

In addition Chens team found that FTO also plays a critical role in various types of solid tumors and FTO inhibitors show potent anti-tumor efficacy in treating multiple types of solid tumors, highlighting the broad therapeutic potential of targeting FTO in treating various types of cancers.

Targeting dysregulated m6A machinery with effective inhibitors (bisantrene) alone or in combination with other therapeutics represents attractive novel approach to treat leukemia patients, especially the refractory / relapsed patients who are resistant to currently available therapies. (note our Israel trial is targeting relapsed / refractory patients).

IMO this independent paper from a leading key opinion leader further de-risks RAC pillars 1 2 & 3

BUY HODL HELD ladies & gentlemen!